Saccharide dendritic cluster compounds as inhibitors of BACE-1

Abstract

The invention relates to dendritic compounds, the use of these compounds as pharmaceuticals, pharmaceutical compositions containing the compounds, processes for preparing the compounds, and methods of treating diseases or conditions in which it is desirable to inhibit β-secretase.

The invention claimed is: 
     
       1. A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         R 3  is a radical of formula (iv) or a radical of formula (iv)(a) 
       
       
         
           
           
               
               
           
         
         R 5  is a radical of formula (v), (vi), (vii), (viii) or (ix): 
       
       
         
           
           
               
               
           
         
         j is an integer from 1 to 6; 
         k is an integer from 0 to 5; 
         R 6  is H, SO 3 H, an acyl group which is optionally radiolabelled, or R 6  is C(═O)R 8  where R 8  is aryl or aralkyl; 
         R 7  is H or SO 3 H; 
         and: 
         Y is O; 
         B is O; 
         R 1  and R 2  are absent; and 
         either A, E, D and X are all CH 2 ; or A, D and X are all CH 2  and E is (CH 2 CH 2 O) t   # CH 2    
         wherein  #  indicates a point of attachment of E to its adjacent carbonyl group; 
         t is an integer from 1 to 10; 
         or: 
         Y is C; 
         R 1  and R 2  are both H; and 
         A, E, B and D are CH 2  and X is O; 
         or: 
         Y is C; 
         A is (CH 2 ) u    
         R 1  and R 2  are both H; 
         B, X, D and E are all absent; and 
         u is an integer from 1 to 10; 
         or: 
         Y is C; 
         X is O; 
         B is (CH 2 ) p ; 
         A, E and D are all CH 2 ; 
         R 1  is H, NHZ or C 1-6 alkyl and R 2  is a radical of formula (i), a radical of formula (ii) or a radical of formula (ii)(a) 
       
       
         
           
           
               
               
           
         
         Z is H, acyl, C(OXCH 2 ) w N(H)G, *CH 3 *C(O)— where *C denotes  13 C or  14 C, 5-TAMRA (4-carboxytetramethylrhodamine), Fluorescein (resorcinolphthalein), Alexa Fluor 350 (7-amino-4-methyl-6-sulfocoumarin-3-acetic acid), BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) or Alkyne MegaStokes dye 608 (1-{3-{[4-(2-cyclooctyn-1-ylmethyl)benzoyl]amino}propyl}-4-{2-[4-(dimethylamino)phenyl]ethenyl}pyridinium hexafluorophosphate); 
         w is an integer from 1 to 11; and 
         G is H, acyl,Boc (t-butoxycarbonyl), Troc (2,2,2-trichloroethyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl),*CH 3 *C(O)— where *C denotes  13 C or  14 C, 5-TAMRA (4-carboxytetramethylrhodamine), Fluorescein (resorcinolphthalein), Alexa Fluor 350 (7-amino-4-methyl-6-sulfocoumarin-3-acetic acid), BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) or Alkyne MegaStokes dye 608 (1-{3-{[4-(2-cyclooctyn-1-ylmethyl)benzoyl]amino}propyl}-4-{2-[4-(dimethylamino)phenyl]ethenyl}pyridinium hexafluorophosphate); 
         or: 
         Y is C; 
         X is O; 
         B is (CH 2 ) p ; 
         A, E and D are all CH 2 ; and 
         R 1  and R 2 , both the same, are a radical of formula (i), a radical of formula (ii) or a radical of formula (ii)(a) 
       
       
         
           
           
               
               
           
         
         and: 
         each T is independently selected from the group consisting of (CH 2 CH 2 O) x CH 2 CH 2  and CH 2 , wherein each T is CH 2  or at least one T is (CH 2 CH 2 O) x CH 2 CH 2 ; 
         each x is independently an integer from 1 to 12; 
         n is an integer from 1 to 11, provided that when T is (CH 2 CH 2 O) x CH 2 CH 2  then n is 1; 
         q is an integer from 1 to 11; 
         m is an integer from 1 to 11, provided that when T is (CH 2 CH 2 O) x CH 2 CH 2  then m is 1; and 
         p is an integer from 1 to 5; 
         or a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
       
     
     
       2. The compound of  claim 1 , wherein each T is CH 2 . 
     
     
       3. The compound of  claim 1 , wherein R 3  is a radical of formula (iv). 
     
     
       4. The compound of  claim 1 , wherein R 1  and R 2 , both the same, are a radical of formula (i) or a radical of formula (ii), or wherein R 1  is H, NHZ or C 1-6 alkyl and R 2  is a radical of formula (i) or a radical of formula (ii). 
     
     
       5. The compound of  claim 1 , wherein at least one T is (CH 2 CH 2 O) x CH 2 CH 2 . 
     
     
       6. The compound of  claim 1 , wherein R 5  is a radical of formula (vi), (vii), (viii) or (ix) wherein radical (vi), (vii), (viii) or (ix) contains no ido-form saccharide units. 
     
     
       7. The compound of  claim 1 , wherein R 5  is a radical of formula (vi), (vii), (viii) or (ix) wherein radical (vi), (vii), (viii) or (ix) contains no gluco-form saccharide units. 
     
     
       8. The compound of  claim 1 , wherein R 5  is a radical of formula (vi), (vii), (viii) or (ix) wherein radical (vi), (vii), (viii) or (ix) comprises a mixture of gluco-form and ido-form saccharide units. 
     
     
       9. The compound of  claim 1 , wherein R 1  and R 2 , both the same, are a radical of formula (ii)(a) 
       
         
           
           
               
               
           
         
       
     
     
       10. The compound of  claim 1 , wherein Y is O; B is O; R 1  and R 2  are absent; and either A, E, D and X are all CH 2  or A, D and X are all CH 2  and E is (CH 2 CH 2 O) t CH 2 ; and t is an integer from 1 to 10. 
     
     
       11. The compound of  claim 1 , wherein Y is C; R 1  and R 2  are both H; A, E, B and D are CH 2  and X is O. 
     
     
       12. The compound of  claim 1 , wherein Y is C; A is (CH 2 ) u ; R 1  and R 2  are both H; B, X, D and E are all absent; and u is an integer from 1 to 10. 
     
     
       13. The compound of  claim 1 , wherein:
 Y is C; X is O; A, E and D are all CH 2 , B is (CH 2 ) p ; 
 R 1  is H, NHZ or C 1-6 alkyl;
 R 2  is a radical of formula (i), a radical of formula (ii) or a radical of formula (ii)(a) 
 
 
       
         
           
           
               
               
           
         
         Z is H, acyl, CO(CH 2 ) w N(H)G, *CH 3 *CO— where *C denotes  13 C or  14 C, 4-carboxytetramethylrhodamine, resorcinolphthalein, 7-amino-4-methyl-6-sulfocoumarin-3-acetic acid, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene or 1-{3-{[4-(2-cyclooctyn-1-ylmethyl)benzoyl]amino}propyl}-4-{2-[4-(dimethylamino)phenyl]ethenyl}pyridinium hexafluorophosphate; 
         w is an integer from 1 to 11; 
         G is H, acyl, t-butoxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl,*CH 3 *CO— where *C denotes  13 C or  14 C, 4-carboxytetramethylrhodamine, resorcinolphthalein, 7-amino-4-methyl-6-sulfocoumarin-3-acetic acid, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene or 1-{3-{[4-(2-cyclooctyn-1-ylmethyl)benzoyl]amino}propyl}-4-{2-[4-(dimethylamino)phenyl]ethenyl}pyridinium hexafluorophosphate. 
       
     
     
       14. The compound of  claim 1 , wherein Y is C; X is O; A, E and D are all CH 2 ; B is (CH 2 ) p ;
 R 1  and R 2 , both the same, are a radical of formula (i), a radical of formula (ii) or a radical of formula (ii)(a) 
 
       
         
           
           
               
               
           
         
       
     
     
       15. The compound of  claim 1 , wherein R 5  is a radical of formula (viii) wherein j is 1. 
     
     
       16. The compound of  claim 1 , wherein R 5  is a radical of formula (ix) wherein k is 0 or 1. 
     
     
       17. The compound of  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       18. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of  claim 1  and optionally a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
       19. A method of treating a disease or disorder in which it is desirable to inhibit BACE-1, the method comprising administering a pharmaceutically effective amount of a compound of  claim 1  to a patient requiring treatment, wherein the disease or disorder is senile dementia, pre-senile dementia, multi-infarct dementia or Alzheimer's disease.